This invention relates to a method for the treatment of uterine contractility disorders, such as preterm labor, dysmenorrhea and other menstrual problems (e.g., disfunctional uterine bleeding and protracted labor with a nitric oxide synthase substrate (e.g., L-arginine), a nitric oxide donor or both, alone or in further combination with an agent which inhibits uterine contractility (e.g., a prostaglandin inhibitor, progestin, an oxytocin antagonist or .beta.-agonist). Furthermore, this invention relates to a method for the stimulation of uterine contractility for disorders such as inadequate menses, for inducing abortion or for stimulation of labor or to control postpartum hemorrhage, with nitric oxide inhibitors such as L-NAME (NG-nitro-L-arginine methyl ester), alone or in combination with a progesterone antagonist, mimetic, oxytocin and/or prostaglandin.
Uterine contractility disorders are significant health problems. Dysmenorrhea, painful uterine contractions or cramping during the menstrual period, affects almost all gonadal women. Similarly, preterm labor occurs in a significant proportion (about 10%) of pregnant women and is the leading cause of fetal mortality and morbidity. The etiology of uterine contractility disorders and premature labor are largely unknown and effective therapy to inhibit uterine contractility and prevent the symptoms associated with these diseases are unknown. On the other hand, millions of women undergo therapy to stimulate the uterus to contract during pregnancy for abortion, dystocia or as an aid to assist contractility at term, agents such as antiprogestins, oxytocin and prostaglandin analogs are used for these purposes but their effectiveness is not always certain and their mechanism of action is also unknown.
Recently, nitric oxide has been shown to be endothelium derived relaxing factor (EDRF) from the endothelium of blood vessels. Nitric oxide is considered to be a major mediator in the control of vascular reactivity. Nitric oxide is synthesized from the substrate, L-arginine, by nitric oxide synthase located in endothelial cells. Nitric oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1, isosorbid mononitrate, isosorbid dinitrate, etc.
Treatment of nonpregnant guinea pigs with L-NAME results in increased uterine contractility. Thus, inhibition of nitric oxide synthase-stimulated uterine contractility indicates that the tonic release of nitric oxide maintains the uterus in a quiescent state. Similarly, treatment of pregnant guinea pig with L-NAME induced preterm labor. On the other hand, treatment of rat uterine strips in vitro pregnant guinea pigs with L-arginine inhibited contractions. These studies show that nitric oxide production by the uterus inhibits contractility and a blockade of this synthesis results in increased muscle contractility both in pregnant and nonpregnant animals. Thus, nitric oxide substrates or donors are useful therapeutically to prevent uterine contractility and nitric oxide inhibitors are effective in stimulating uterine contractions.
Since prostaglandin inhibitors, oxytocin antagonists, .beta.-agonists, and progestins (progesterone) are (or may be) used to inhibit uterine contractions, nitric oxide substrates or donors will be particularly useful in combination with these agents to prevent uterine contractions. Similarly, because progesterone antagonists, prostaglandins, prostacyclin-mimetics, cytokines, and oxytocin are (or may be) used to stimulate uterine contractility, they will be particularly helpful in combination with nitric oxide inhibitors to augment uterine contractility.
EP 0 441 119 A2 discloses the use of L-arginine in the treatment of hypertension and other vascular disorders. It suggests that the mechanism by which L-arginine is effective for this purpose is because it may be the physiological precursor of "the most powerful endothelial-derived releasing factor, nitric oxide." The use of L-arginine in combination with other pharmaceutically active agents is not discussed in this publication. Our previous patent application (Ref: SCH 1237) deals with the treatment of preeclampsia and preterm labor with a combination of a progestational agent and a nitric oxide synthase substrate and/or donor but it does not consider the uses of nitric oxide substrates and/or donor alone for treatment of uterine contractility disorders nor does it consider the inhibition of nitric oxide for the use of stimulating uterine contractions for dystocia, abortion, and the stimulation of labor.